Tuvusertib in Astrocytoma With ATRX Mutation

Inclusion Criteria:

1. Written informed consent approved by the Independent Ethics Committee (IEC), priorto the performance of any trial activities.

2. Patients, males and females, ≥ 18 years of age at the time of signing the informedconsent.

3. Patients with Karnofsky performance status (KPS) index > 60% (Appendix 5).

4. Diagnosis of Grade 2-4 astrocytoma, IDH-mutated according to the 2021 WHOclassification.

5. Patients must have confirmed ATRX mutation (IHC or NGS sequencing) and p53 mutation (NGS sequencing). Evaluation of CDKN2A also is required by FISH or NGS.

6. Patients must have progressive disease and evaluable disease according to RANO 2.0criteria. All patients should have MRI contrast enhancement disease.

7. Patients must have undergone previous standard treatment with radiotherapy andchemotherapy (procarbazine, lomustine and vincristine [PCV] or temozolomide [TMZ]).

8. Stable corticosteroid doses during the 2 weeks previous to the first dose oftuvusertib, maximum dose of dexamethasone 4 mg/day or equivalent.

9. Adequate hematologic, hepatic and renal function as follows:

10. Platelet count ≥ 100,000/mm3,

11. Hemoglobin ≥ 9.0 g/dL,

12. Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within thelast 14 days,

13. Total bilirubin level ≤ 1.5 × upper limit of normal (ULN) (if Gilbert'sSyndrome may have total bilirubin > 1.5 × ULN),

14. Aspartate aminotransferase (AST) level ≤ 3 × ULN, and an alanineaminotransferase (ALT) level ≤ 3 × ULN.

15. Serum creatinine ≤ 1.5 × ULN. If serum creatinine is > 1.5 × ULN, creatinineclearance needs to be ≥ 50 mL/min, as estimated by Cockcroft-Gault

16. Contraceptive use by males or females will be consistent with local regulations oncontraception methods for those participating in clinical studies.

17. Patients able to take oral medications.

18. Willingness and ability of patients to comply with the protocol for the duration ofthe study including undergoing treatment as well as availability for scheduledvisits and examinations including follow-up.

Exclusion Criteria:

1. Patients with radiographic recurrence without contrast enhancement by MRI.

2. Leptomeningeal dissemination and/or extracranial metastases.

3. Patients who received more than 1 previous systemic line of treatment forastrocytoma.

4. Patients who received previous treatment with bevacizumab.

5. Persistence of AEs related to any prior treatments that have not recovered to Grade ≤ 1 unless AEs are clinically nonsignificant (e.g. alopecia) and/or stable onsupportive therapy in the opinion of the Investigator.

6. No prior ATR inhibitor and/or CHK1 inhibitor.

7. Concurrent treatment with a non permitted drug/intervention:

8. Prohibited concomitant medication, as listed in Section 7.8.

9. Anticancer treatment within 30 days or 5 half-lives, whichever is shorter,prior to Day 1 of study intervention (6 weeks for nitrosoureas or mitomycin C).

10. Prior palliative radiotherapy to metastatic lesion(s) is permitted provided itwas completed ≥ 12 weeks prior to study intervention administration andparticipants have recovered from all related radiotherapy toxicities to Grade ≤

12. Another investigational drug within 30 days or 5 half-lives, whichever isshorter, prior to start of tuvusertib administration.

13. Increasing dose of corticoids.

14. Received hematopoietic growth factor (e.g., granulocyte colony-stimulatingfactor, erythropoietin) within 14 days prior to the first dose of tuvusertib.

15. Significant cardiac disease:

16. Unstable angina, myocardial infarction, congestive heart failure ≥ stage II) ora coronary revascularization procedure within 180 days of study entry.

17. Calculated QTc average (using the Fridericia correction calculation) of > 450msec for males and > 470 msec for females.

18. Uncontrolled hypertension.

19. Active and/or uncontrolled infection. The following exceptions apply:

20. Participants with HIV infection are eligible if they are on effectiveantiretroviral therapy with undetectable viral load within 6 months, providedthere is no expected drug-drug interaction

21. Participants with evidence of chronic HBV infection are eligible if the HBVviral load is undetectable on suppressive therapy (if indicated), and if theyhave ALT, AST, and total bilirubin levels < ULN, and provided there is noexpected drug-drug interaction

22. Participants with a history of HCV infection are eligible if they have beentreated and cured. For participants with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load, andif they have ALT, AST, and total bilirubin levels < ULN.

23. Treatment with live or live attenuated vaccine within 30 days of dosing.

24. Known hypersensitivity to the components of tuvusertib.

25. Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the patient has not fully recovered from the surgery within 4 weeks of the study intervention.